Apixaban, dabigatran found effective, safe for extended post-VTE therapy

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism in three industry-sponsored randomized clinical trials. The results were published online Feb. 21 in the New England Journal of Medicine.

Both medications also reduced the risk of bleeding complications, the investigators said.

In the first trial, two doses of apixaban were compared against placebo in 2,486 patients with venous thromboembolism who had finished 6-12 months of standard anticoagulation therapy and whose physicians were uncertain whether to stop or continue anticoagulation treatment, said Dr. Giancarlo Agnelli and his associates in the Apixaban after the Initial Management of Pulmonary Embolism and DVT with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study.

Apixaban is an oral factor Xa inhibitor that is administered in fixed doses and doesn’t require laboratory monitoring. The 5-mg (treatment) dose of apixaban has proved effective at preventing stroke in patients with atrial fibrillation, and the 2.5-mg (maintenance) dose has proved effective for thromboprophylaxis after major orthopedic surgery, said Dr. Agnelli of the department of internal and cardiovascular medicine-stroke unit at the University of Perugia (Italy) and his colleagues.

The study subjects were enrolled over a 3-year period at 328 medical centers in 28 countries. They were randomly assigned in double-blind fashion to receive the 2.5-mg dose (840 subjects), the 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year.

The primary efficacy outcome measure was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). Thus, both doses of apixaban significantly decreased the incidence of recurrent VTE, Dr. Agnelli and his associates said (N. Engl. J. Med. 2013 Feb. 21 [doi10.1056/NEJMoa1207541]).

The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Thus, both doses of apixaban were comparable to placebo in rates of major bleeding.

Clinically relevant nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo.

The number of patients who would need to be treated with apixaban to prevent a single episode of recurrent VTE was 14. In contrast, the number who would need to be treated to cause an episode of major or clinically relevant nonmajor bleeding was 200, the investigators noted.

"For patients with venous thromboembolism for whom there is uncertainty about the benefits and risks of continued therapy, the results of this study provide a rationale for continuing anticoagulation therapy for an additional 12 months," they said.

"It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment. Consequently, more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients," the researchers said.

Further research also is needed to determine the risks and benefits of extending anticoagulation therapy beyond the 12-month mark examined in this study, they added.

In a separate report, Dr. Sam Schulman and his associates in the RE-MEDY and RE-SONATE studies examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. These trials were extensions of two previous studies of short-term anticoagulation after venous thromboembolism (N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMoa1113697]).

In RE-MEDY*, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues.

The RE-SONATE* trial, in contrast, involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence, so it was ethical to assess the effect of dabigatran vs. placebo in these patients. The subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries.

In both RE-SONATE and RE-MEDY, the primary efficacy outcome measure was recurrent symptomatic VTE or VTE-related death.

In RE-MEDY, this outcome occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE.

In RE-SONATE, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE.

Dabigatran was associated with markedly fewer major bleeding events (0.9% vs. 1.8%) and clinically relevant bleeding events (5.6% vs. 10.2%) than was warfarin. However, the drug was associated with more major or clinically relevant bleeding events than was placebo (5.3% vs 1.8%).

In addition, there was a higher rate of acute coronary events with dabigatran (0.9%) than with warfarin (0.2%), although the number of affected patients was small. A recent meta-analysis of seven noninferiority trials also showed a significantly higher risk of MI or acute coronary syndromes with dabigatran than with the comparators. "Whether dabigatran increases the risk of MI is therefore still unclear," Dr. Schulman and his associates said.

AMPLIFY-EXT was funded by Bristol-Myers Squibb (BMS) and Pfizer; Dr. Agnelli reported ties to Bayer, Boehringer Ingelheim (BI), Daiichi Sankyo, BMS, and Sanofi-Aventis, and his associates reported ties to numerous industry sources. RE-MEDY and RE-SONATE were funded by BI; Dr. Schulman and his associates reported ties to numerous industry sources.

UPDATED 2/21: An earlier version of this article transposed the trial names in this instance only. The names were correct in all other instances.

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism in three industry-sponsored randomized clinical trials. The results were published online Feb. 21 in the New England Journal of Medicine.

Both medications also reduced the risk of bleeding complications, the investigators said.

In the first trial, two doses of apixaban were compared against placebo in 2,486 patients with venous thromboembolism who had finished 6-12 months of standard anticoagulation therapy and whose physicians were uncertain whether to stop or continue anticoagulation treatment, said Dr. Giancarlo Agnelli and his associates in the Apixaban after the Initial Management of Pulmonary Embolism and DVT with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study.

Apixaban is an oral factor Xa inhibitor that is administered in fixed doses and doesn’t require laboratory monitoring. The 5-mg (treatment) dose of apixaban has proved effective at preventing stroke in patients with atrial fibrillation, and the 2.5-mg (maintenance) dose has proved effective for thromboprophylaxis after major orthopedic surgery, said Dr. Agnelli of the department of internal and cardiovascular medicine-stroke unit at the University of Perugia (Italy) and his colleagues.

The study subjects were enrolled over a 3-year period at 328 medical centers in 28 countries. They were randomly assigned in double-blind fashion to receive the 2.5-mg dose (840 subjects), the 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year.

The primary efficacy outcome measure was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). Thus, both doses of apixaban significantly decreased the incidence of recurrent VTE, Dr. Agnelli and his associates said (N. Engl. J. Med. 2013 Feb. 21 [doi10.1056/NEJMoa1207541]).

The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Thus, both doses of apixaban were comparable to placebo in rates of major bleeding.

Clinically relevant nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo.

The number of patients who would need to be treated with apixaban to prevent a single episode of recurrent VTE was 14. In contrast, the number who would need to be treated to cause an episode of major or clinically relevant nonmajor bleeding was 200, the investigators noted.

"For patients with venous thromboembolism for whom there is uncertainty about the benefits and risks of continued therapy, the results of this study provide a rationale for continuing anticoagulation therapy for an additional 12 months," they said.

"It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment. Consequently, more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients," the researchers said.

Further research also is needed to determine the risks and benefits of extending anticoagulation therapy beyond the 12-month mark examined in this study, they added.

In a separate report, Dr. Sam Schulman and his associates in the RE-MEDY and RE-SONATE studies examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. These trials were extensions of two previous studies of short-term anticoagulation after venous thromboembolism (N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMoa1113697]).

In RE-MEDY*, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues.

The RE-SONATE* trial, in contrast, involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence, so it was ethical to assess the effect of dabigatran vs. placebo in these patients. The subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries.

In both RE-SONATE and RE-MEDY, the primary efficacy outcome measure was recurrent symptomatic VTE or VTE-related death.

In RE-MEDY, this outcome occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE.

In RE-SONATE, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE.

Dabigatran was associated with markedly fewer major bleeding events (0.9% vs. 1.8%) and clinically relevant bleeding events (5.6% vs. 10.2%) than was warfarin. However, the drug was associated with more major or clinically relevant bleeding events than was placebo (5.3% vs 1.8%).

In addition, there was a higher rate of acute coronary events with dabigatran (0.9%) than with warfarin (0.2%), although the number of affected patients was small. A recent meta-analysis of seven noninferiority trials also showed a significantly higher risk of MI or acute coronary syndromes with dabigatran than with the comparators. "Whether dabigatran increases the risk of MI is therefore still unclear," Dr. Schulman and his associates said.

AMPLIFY-EXT was funded by Bristol-Myers Squibb (BMS) and Pfizer; Dr. Agnelli reported ties to Bayer, Boehringer Ingelheim (BI), Daiichi Sankyo, BMS, and Sanofi-Aventis, and his associates reported ties to numerous industry sources. RE-MEDY and RE-SONATE were funded by BI; Dr. Schulman and his associates reported ties to numerous industry sources.

UPDATED 2/21: An earlier version of this article transposed the trial names in this instance only. The names were correct in all other instances.

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism in three industry-sponsored randomized clinical trials. The results were published online Feb. 21 in the New England Journal of Medicine.

Both medications also reduced the risk of bleeding complications, the investigators said.

In the first trial, two doses of apixaban were compared against placebo in 2,486 patients with venous thromboembolism who had finished 6-12 months of standard anticoagulation therapy and whose physicians were uncertain whether to stop or continue anticoagulation treatment, said Dr. Giancarlo Agnelli and his associates in the Apixaban after the Initial Management of Pulmonary Embolism and DVT with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study.

Apixaban is an oral factor Xa inhibitor that is administered in fixed doses and doesn’t require laboratory monitoring. The 5-mg (treatment) dose of apixaban has proved effective at preventing stroke in patients with atrial fibrillation, and the 2.5-mg (maintenance) dose has proved effective for thromboprophylaxis after major orthopedic surgery, said Dr. Agnelli of the department of internal and cardiovascular medicine-stroke unit at the University of Perugia (Italy) and his colleagues.

The study subjects were enrolled over a 3-year period at 328 medical centers in 28 countries. They were randomly assigned in double-blind fashion to receive the 2.5-mg dose (840 subjects), the 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year.

The primary efficacy outcome measure was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). Thus, both doses of apixaban significantly decreased the incidence of recurrent VTE, Dr. Agnelli and his associates said (N. Engl. J. Med. 2013 Feb. 21 [doi10.1056/NEJMoa1207541]).

The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Thus, both doses of apixaban were comparable to placebo in rates of major bleeding.

Clinically relevant nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo.

The number of patients who would need to be treated with apixaban to prevent a single episode of recurrent VTE was 14. In contrast, the number who would need to be treated to cause an episode of major or clinically relevant nonmajor bleeding was 200, the investigators noted.

"For patients with venous thromboembolism for whom there is uncertainty about the benefits and risks of continued therapy, the results of this study provide a rationale for continuing anticoagulation therapy for an additional 12 months," they said.

"It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment. Consequently, more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients," the researchers said.

Further research also is needed to determine the risks and benefits of extending anticoagulation therapy beyond the 12-month mark examined in this study, they added.

In a separate report, Dr. Sam Schulman and his associates in the RE-MEDY and RE-SONATE studies examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. These trials were extensions of two previous studies of short-term anticoagulation after venous thromboembolism (N. Engl. J. Med. 2013 Feb. 21 [doi:10.1056/NEJMoa1113697]).

In RE-MEDY*, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues.

The RE-SONATE* trial, in contrast, involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence, so it was ethical to assess the effect of dabigatran vs. placebo in these patients. The subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries.

In both RE-SONATE and RE-MEDY, the primary efficacy outcome measure was recurrent symptomatic VTE or VTE-related death.

In RE-MEDY, this outcome occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE.

In RE-SONATE, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE.

Dabigatran was associated with markedly fewer major bleeding events (0.9% vs. 1.8%) and clinically relevant bleeding events (5.6% vs. 10.2%) than was warfarin. However, the drug was associated with more major or clinically relevant bleeding events than was placebo (5.3% vs 1.8%).

In addition, there was a higher rate of acute coronary events with dabigatran (0.9%) than with warfarin (0.2%), although the number of affected patients was small. A recent meta-analysis of seven noninferiority trials also showed a significantly higher risk of MI or acute coronary syndromes with dabigatran than with the comparators. "Whether dabigatran increases the risk of MI is therefore still unclear," Dr. Schulman and his associates said.

AMPLIFY-EXT was funded by Bristol-Myers Squibb (BMS) and Pfizer; Dr. Agnelli reported ties to Bayer, Boehringer Ingelheim (BI), Daiichi Sankyo, BMS, and Sanofi-Aventis, and his associates reported ties to numerous industry sources. RE-MEDY and RE-SONATE were funded by BI; Dr. Schulman and his associates reported ties to numerous industry sources.

UPDATED 2/21: An earlier version of this article transposed the trial names in this instance only. The names were correct in all other instances.